Growth (or neurotrophic) factors promote the differentiation, growth and survival of numerous peripheral and central nervous system neurons during development and adulthood. The molecular characteristics, regulation and signal transduction mechanism for a number of neurotrophic factors have been identified. The most therapeutically promising of these molecules are nerve growth factor (NGF), brain-derived neurotrophic factor (BNDF), ciliary neurotrophic factor (CNTF), basic fibroblast growth factor (bFGF), insulin-like growth factor-I (IGF-I), and glial cell-line derived neurotrophic factor (GDNF).
Available data suggests that neurotrophic factors will be useful in the treatment of neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis. Additionally neurotrophic factors have shown beneficial effects in animal models of peripheral nerve damage and toxin induced neuropathies (CNS Drugs, 2(6), 465-478 (1994)).
Various rat studies predict that compounds mimicking or enhancing the function of NGF can rescue septal colinergic neurons and alleviate benign forgetfulness and the memory impairment seen in senile dementia ( Science, Vol. 264, 772-774 (1994)).
Recent studies have shown that NGF has a neuroprotective effect on hippocampal neurons after cerebral ischaemia, which predicts a potential therapeutic role for NGF in the treatment of cerebral ischaemic neuronal damage (NeuroReport, vol. 6, No 4, 669-672 (1995)).
Growth factors initiate their biological action by binding to specific cell surface receptors. Binding of the growth factor to its receptor activates the intracellular signal transduction, leading to the generation of various second messengers and activation of enzyme cascades, involving tyrosine kinases and protein kinase C, and culminates in a biological effect. The intracellular signal transduction pathway is not yet fully understood.
NGF and related neurotrophins are large peptides, which makes them unlikely therapeutic candidates. Poor pharmacokinetic parameters (e.g. poor oral absorption and short in vivo half life), and administration to the target organs represent the major problems.
The identification of compounds with physicochemical properties different from the neurotrophins but capable of interaction with the neurotrophin-receptors is considered to be extremely important for the development of effective treatments of diseases and disorders responsive to neurotrophic factors.
The inventors of the present invention have found that the 1-(4-piperidyl)-benzimidazoles of formula (I) possess valuable neurotrophic activity. The neurotrophic activity found by the inventors of the present invention has not been ascribed to a specific step in the interaction between NGF and its receptor or in the NGF signal transduction pathway.
The neurotrophic activity of the compounds of formula (I), make them useful in the treatment of various nerve degenerative diseases, such as for example Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis, and in alleviating benign forgetfulness and the memory impairment seen in senile dementia or in connection with neurodegenerative diseases. Furthermore, the compounds are indicated to be useful in the treatment of neuropathy and especially peripheral neuropathy caused by e.g. genetic abnormalities and other conditions such as diabetes, polio, herpes and AIDS, and most especially neuropathy and peripheral neuropathy experienced by most cancer patients after or during chemotherapy.
The compounds of formula (I) are considered to be particularly useful in the treatment of traumatic lesions of peripheral nerves, the medulla, and/or the spinal cord, and in the treatment of cerebral ischaemia, e.g. ischaemic neuronal damage following cardiac arrest, stroke, or postasphyxial brain damage in newborns, or following near-drowning.